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Preface

As the World Health Organization estimates that depression will become the second leading cause of death by the year 2020
– due primarily to complications arising from stress and the cardiovascular system – the need to develop novel and more effective
treatment strategies for patients suffering with mood disorders has never been more paramount. Current treatment options for
depressed patients include a variety of molecules designed to exclusively elevate central nervous system levels of monoamines
such as serotonin (5-HT). These classes include the monoamine oxidase inhibitors and tricyclics and are exemplified by the
selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin/norepinephrine reuptake inhibitors (SNRIs). While these
medicines are moderately effective in some patient populations, there are still considerable limitations associated with all
commercially available antidepressants. These drawbacks include, but are not limited to, delayed onset of efficacy, treatment
resistance in many patients, and deleterious side effects such as emesis and sexual dysfunction. The focus of this book is
to review the current landscape and state of the field for depression research with an eye towards shedding light on where
the future of mood disorders research is headed in terms of novel therapeutic targets, preclinical model development, exploring
depression endophenotypes, and medicinal chemistry strategies. Undoubtedly all of these disciplines, as well as others including
genetics and translational medicine approaches, will need to successfully collaborate to help build a better understanding
of disease etiology, patient stratification, and treatment. As depression research has evolved over the past 50 years, the
next decade will be instrumental in facilitating a move beyond our current understanding and pharmacological treatment options,
and strive to discover and develop more personalized and effective treatment options for the millions of patients suffering
from chronic and debilitating mood disorders.

Chad E. Beyer, PhD, MBA

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

Developing novel animal models of depression

Abstract

Although the mechanism of action of current antidepressant drugs is well known, 30% of patients remain refractory to treatment.
There are examples of recent failures of antidepressant clinical development programs that reinitiate the discussion on the
reliability, or predictability of animal models of major depressive disorder. The comorbid expression of depression is well
known in many neurological and psychiatric diseases, including drug abuse. Symptoms such as anhedonia, hypo- or hyperlocomotor
activity, sleep disturbances, and weight loss can be measured in animals, but the overreliance on such readouts may lead to
misinterpretations of their relevance to the clinical situation. Existing models are mainly based, or could be considered
to have an overreliance, on the putative involvement of monoaminergic systems. Data recorded from these existing models do
result in clinical candidate nomination, but when such compounds reach the clinic, data often do not fully meet expectations.
From a preclinical point of view, the integration of the range of established and novel technologies, such as monitoring dynamic
changes in extracellular neurotransmitters, behavioral readouts, electrophysiological recordings, and brain scanning (e.g.
using functional magnetic resonance imaging and spectroscopy, PET, SPECT imaging) is critically needed in the development
of new animal models, as is the translation of such approaches to the clinic and vice versa. This integration is needed across
the gamut of indication areas of key interest.